Respiratory syncytial virus (RSV), a member of the Pneumovirus genus of the Paramyxoviridae family, is an important cause of respiratory disease in infants and children (Connors, M., et al., J. of Virol., 66:7444-7451 (1992). The immunological basis for the differing susceptibility among individuals, and for the limited age range at which severe illness occurs, remains unclear.
The major impediment to advancing new candidate vaccines directed against RSV to clinical trials is an incomplete understanding of the vaccine-enhanced illness caused by formalin-inactivated RSV vaccines in the 1960's. Clinical trials of a formalin-activated alum-precipitated RSV vaccine in the 1960's showed that the vaccine elicited complement-binding antibodies but failed to protect against infection in children. In addition, the illness after subsequent infection was unusually severe with some deaths, and an increased rate of hospitalization (Kapikian, A. Z., et al. Amer. J. Epidem., 89:405 (1969); Fulginti, V. A., et al, Amer. J. Epidem., 89:435 (1969); Kim, W. H., Amer. J. Epidemol., 89:422 (1969); Chin, J. R., et al. Amer. J. Epidem., 89:449 (1969)). A similar enhanced illness can be induced in mice previously immunized with the formalin-inactivated vaccine upon RSV infection, but not in mice immunized with live RSV (Conners, M., et al., J. Vilrol. 66:7441 (1992); Graham, B. S., et al., Immunol. 151:2032 (1993); Alwan, W. H., et al., J. Exp. Med. 179:81 (1994)). Clinical trials of live attenuated RSV vaccine products have not been associated with enhanced illness. Although the live RSV vaccines did not result in enhanced pulmonary disease upon natural infection, the vaccines were, in other respects, as equally unsuccessful as the formalin-inactivated alum-precipitated RSV vaccines (Kim, W. H., et al., Pediatrics, 48:745 (1971); Kim, W. H., et al., Pediatrics, 52:56 (1973); Belshe, R. B., et al., J. Infect. Dis., 145:311 (1982); Wright, R. B., et al., Infect. Immun., 37:397 (1982). Temperature-sensitive mutants of RSV, cold-adapted RSV or live RSV given parenterally have been considered unsuccessful as vaccines because of high rates of reversion to wild-type, unacceptable virulence or lack of immunogenicity in the appropriate age group (Graham, B. S., et al., J. of Immun., 151:2032-2040 (1993).
Thus, a need exists for development of efficacious methods of vaccination against RSV and for vaccine compositions.